Episode Transcript Arpita: 0:11 Hi everyone, and welcome back to the Smart Tea Podcast, where we talk about the lives of scientists and innovators who shape the world. How are you doing, Aarati? Aarati: 0:19 I'm doing pretty well, Arpita. How are you? Arpita: 0:23 I'm okay. I feel like we're having some cozy vibes with the weather right now. Aarati: 0:27 Yeah. Arpita: 0:28 It's been just like nonstop rain, and so we have candles going, we have the heater running, and it feels like kind of cozy vibes. Yeah. What about you guys? Aarati: 0:37 Yeah, same. I feel like fall really snuck up on me for some reason. I don't know why, but I'm just like, why am I so cold? All right, it's not summer anymore. I should probably pull out my heavy jacket and my heavy sweaters. And for some reason in my mind, I'm really resisting that. And then I regret it Arpita: 0:56 Well, you like the warm weather. Aarati: 0:57 I do like the warm weather. And I think part of me is in denial that it's over. And I'm like, that wasn't enough. Where's, you know, where's my other 90 degree days. Arpita: 1:08 Last year, Logan bought a bunch of like, honestly, just like kind of a little bigger than a piece of paper heating pads that are electric. Aarati: 1:16 Oh my gosh. Arpita: 1:17 That sometimes people will use for like back pain or cramps. Yeah. And. We now have three. One is on my desk chair, so I sit on it, and then we have one on the couch that the cats sit on, but it's honestly so great. It's kind of like, you know, when you get into your car and you have heated seats? Aarati: 1:32 Yes. Arpita: 1:32 It's like that, but like in your desk chair or like on the couch, which is... Aarati: 1:36 Oh my god. Arpita: 1:37 ...perfect, because then you put a blanket over it and now you've just created this incubator and you're just roasting on the couch and it feels amazing. So, maybe that'll be your Christmas present, Aarati. I'll just Amazon you a heating pad and you can sit on it for all of winter. Aarati: 1:53 Yes, I have a huge, like, hoodie blanket that I use, like, Like a Snuggie, but like, it's not, it's a knockoff Snuggie, I guess. Yeah, Arpita: 2:02 Like off brand Snuggie. Aarati: 2:03 Yeah, like from Amazon. And I just live in that thing. It's, it's just so amazing. It keeps me so warm and I'm so happy in it. But yeah, this weekend I went to like a water lantern festival that was outside and they had to wait until it got dark so that you could see the lit up lanterns on the water and I was not dressed appropriately. I was so cold. I was wearing my sweater, but like, you know, I was, I was freezing and I was like, the sun has set. The sun has set. Let's do this and get out of here. I'm so cold. And I was like, yeah, I really need to just like come to terms with the fact that it's not fall. It's winter. Arpita: 2:43 Does Kyro keep you warm? Aarati: 2:44 No, he's not a snuggle. He's not a snuggly dog. Arpita: 2:47 Oh yeah, he's not a snuggly dog. Aarati: 2:48 He'll put up with it. Like, I'll hug him and he'll be like, okay, fine. But he's very happy in his own bed and I'm like, okay. I see how it is. Arpita: 2:56 The utility is not there for sure. Aarati: 2:58 Yeah. And he's also like, he doesn't like having blankets on him either. Like, I've felt so cold before and I'm like, Oh my gosh, Kyro must be feeling so cold. Let me put a blanket on him. And he's like, why have you done this to me? And he like crawls out of it as soon as I am not looking. He's like, okay, enough of that. Arpita: 3:18 I feel like that's like, probably the shepherd, you know, he's just like, no, he's like, yeah, this is not, I don't need this. Aarati: 3:24 I mean, he does have a fur coat at all times, so I guess.. Arpita: 3:27 It's true, but yeah. Well, let's have a little cozy story. Shall we? Aarati: 3:33 Yes. Arpita: 3:34 Who are we talking about today? Aarati: 3:35 You know, I'm still not really over the election. And so I felt like I just needed a little bit of girl power. Arpita: 3:42 Nice. Aarati: 3:42 Yeah, so today we are going to be talking about Brigitte Askonas. And she basically is the mother of immunology. And she really earns that title. She's just crazy smart and just basically everything we know, like the foundations of immunology, it's thanks to her. Arpita: 4:05 That's amazing. Okay, I'm super excited to hear. Aarati: 4:08 Yeah, this is a little scary for me because I feel like I have a mental block when it comes to immunology for some reason. Arpita: 4:14 Don't we all a little bit though? Like I see the T cells and I see the B cells, the cytokines. I'm just like... Aarati: 4:21 Like what is happening? Why are there so many cells involved in keeping us safe and healthy? Yeah, but she was all over it. She was all over it. So I'm going to do my best and really try to explain the immune system So Brigitte, who went by Ita, was born in Vienna, Austria on April 1st, 1923. Her parents, Carl, Frederick, and Rose, immigrated to Vienna from Czechoslovakia. And they were part of a prominent Jewish community there. There isn't a ton of information about Ita's childhood. We know that she had an older brother, Fred, and her father and uncle owned a chain of knitting mills across Europe. And her mother had studied fine art, and she passed down her love of art and music to Ita. So it sounds like the family was pretty well off in general if they owned this, you know, chain of knitting mills. The mothers into fine art, they built up a collection of art as well, and both parents were very supportive of their children. So it just kind of sounds like a very happy childhood. Arpita: 5:27 Uh huh. Aarati: 5:29 However, when Ita was 15, Austria was annexed by Germany just before World War II, and so Ida and her family had to flee, and they had to leave behind their house and most of their art collection. They hopped around Europe for a bit, and then they fled to New York, but they didn't have a visa to stay in the U. S., so they ended up settling in Canada in 1940. And so by this time, Ita is 17. So she's starting to think about college and, um, what she wants to do in life, but she wasn't really drawn to any one field of study because her mom was like into art and music. And she loved that. She loved languages. She loved literature. She liked nature. She liked biology, but she wasn't really like sure what she wanted to major in. So she spent 2 years at Wellesley College in Massachusetts before transferring to McGill University. Arpita: 6:27 Oh nice. Aarati: 6:27 And even at McGill she kind of spent some time undecided about what she wanted to study. Until she started taking classes from a biochemistry professor, who was also the Dean of Science, Dr. David Thompson. And Ita thought he was, quote,"The most brilliant lecturer I've ever heard speak with a marvelous sense of humor." Arpita: 6:47 Oh, love that. Aarati: 6:48 Yeah. And so solely because of his influence, she decided to pursue her degree in biochemistry. Arpita: 6:55 Honestly, I can't relate. I had a terrible biochemistry teacher in college. Aarati: 6:59 Yeah. Arpita: 7:00 Cannot relate. That class was so hard for me. And then I did take organic chemistry also for like a short bit there. And I was like, get me out of here. That was actually, no, I almost failed two classes in college. One was organic chemistry 2. Then the other was physics. It was like optics and waves. Aarati: 7:20 Oh, yeah. Arpita: 7:21 Like there's like kinematics. There's like, whatever. There's like different like section. It was like the optics and weight. Those were the two classes I almost failed in college. Aarati: 7:28 Yeah. Organic chemistry. Man, that's, that's like the class that, you know, everyone drops out and it's like, I can no longer be a science major. Organic chemistry is crazy. Arpita: 7:39 I feel like they did it on purpose. Like, they must have done it on purpose. Like, I think about it now and like, sometimes it'll like, pop up, you know, every now and then, like principles of organic chemistry. But I'm like, this makes a lot of sense. Like, I feel like if someone had explained it to me properly, I would have been fine with it. But there's also this, like, intimidation factor around it. Aarati: 7:56 Yes. Arpita: 7:56 And I feel like the tests were, like, unnecessarily hard on purpose. Aarati: 7:59 Yeah. They definitely made it harder than it needed to be. Yeah. Arpita: 8:02 They made it way harder than it needed to be. I feel like it was actually not that bad. Aarati: 8:06 Yeah, no, it wasn't. Like I remember, I was taking an organic chemistry class once and I was studying for an exam with my friend and so I was reading the textbook like trying desperately to understand what was going on. Arpita: 8:19 That's when you know, it's bad, but yeah. Aarati: 8:20 Yeah. And she's like memorizing whatever was taught to us and and they had given us some like crazy mnemonic device that had 15 exceptions to the rule, you know, and she was like trying to memorize all those exceptions. And I was just like, you know, I'm, I'm not good at that. I'm not good at memorizing things. And so I was like trying to understand like what's going on. I read the textbook and it took me a while, but I finally understood what the textbook was saying. And I'm like, Oh my God, if you just go through like these five steps and you answer these five questions about the reaction that you're studying, you get the answer right every single time. There are no exceptions. Like this is how it works because that's how nature works. Because... Arpita: 9:00 Rather than like going the long way around. Yeah. Aarati: 9:03 And creating some weird mnemonic devices that has 15 exceptions, why don't you just teach us how it actually works? Yeah. And I was just like, Oh, this makes so much more sense. But then I told my friend about it, who I was studying with. And she was like, I'm just going to memorize it. And I'm just like, why though? This is so much easier. And it makes so much more sense. Yeah, but I don't know what they're doing with, with O chem, but I actually majored in biochemistry because my dad was a biochemistry major also and I was just like, I'll just do that and then I'm like, what have I gotten myself into? Oh no! But Ita decided to pursue her degree in biochemistry. And after five years at McGill, she graduated with a masters. So at the time she graduated. There was another professor, Dr. Karl Stern, who had just been appointed to the Allen Memorial Institute of Psychiatry and was conducting job interviews looking for someone in biochemistry to join his lab. So Ita went to this interview and that was being held in Dean Thompson's office. And during the interview, she starts laughing uncontrollably at a cartoon that Dean Thomas had on his wall. The cartoon was by this guy named James Thurber, and it showed a psychiatrist that was sitting at his desk, but instead of a normal human head, the psychiatrist had a rabbit's head and there's a woman sitting across from him and the psychiatrist rabbit guy is saying,"You said a moment ago that everybody you look at seems to be a rabbit. Now what did you mean by that, Mrs. Sprague?" And apparently Ita found this so hilarious. That she couldn't stop laughing. I didn't get it either. I was just like, I looked at the cartoon, like, I looked it up and I'm just like, what? I'm like, maybe this is like 1940s humor or something. Arpita: 10:56 Like, he's supposed to, like, he is a rabbit and he's saying, you think everyone looks like a rabbit? So he's, like, she's not hallucinating. It's real. Aarati: 11:05 Or maybe she is hallucinating, and we're seeing her perspective, and it's like literally everyone's a rabbit? I don't know. I didn't understand it either, but she found it hilarious. She was just like Arpita: 11:17 And then also started laughing during an interview. Aarati: 11:19 During an interview, she was like laughing so hard, she couldn't stop laughing at this cartoon. Arpita: 11:24 Interesting tactic, but okay. Aarati: 11:26 Yeah, but it worked. Dr. Stern was like, I like your sense of humor, I will hire you. And so, I mean, that's how Ita tells the story of how she got her first job. But, you know, I'm sure Dr. Stern was very impressed with her knowledge and passion for science and her, like, you know, biochemistry acumen. Arpita: 11:46 Speaking of sense of humor, I one time during a grad school interview had someone straight up ask me, tell me a joke. And I was like, what? Aarati: 11:55 What? Arpita: 11:56 Yeah, Aarati: 11:57 That's so random. Arpita: 11:59 Isn't that terrifying? And then like also, I was like 21 or 22, you know, like I was, Aarati: 12:05 oh my God. Arpita: 12:05 Like already petrified to be in this room, you know? Like, I was like, I shouldn't be in this room to begin with. Aarati: 12:10 Yeah. Arpita: 12:10 Like I'm already feeling horrendous things. And I was just like, how do you want me to answer that question? Aarati: 12:18 Yeah. Did you tell them a joke? Arpita: 12:20 I don't even remember what I said. I honestly, I think I blacked out. I don't even know what I said. But I have, now I have two back pocket jokes. Aarati: 12:29 Are they science jokes? No, not really. Arpita: 12:35 One is inappropriate and one is very G rated. Aarati: 12:38 Okay. Arpita: 12:39 So, you know, it's audience specific. Aarati: 12:41 Yes, it depends on who you're talking to. That's a good tactic though. Arpita: 12:45 Thank you. Aarati: 12:46 So, yeah, so she got this job and she starts working on the biochemistry of dementia with Dr. Stern. Dr. Stern thought there must be some chemical imbalances in the brain that were leading to dementia, but since it's the 1940s, they didn't really have good enough tools to properly test these theories. And pretty soon, Ita also realized that her master's degree just wasn't gonna cut it in addition to not having the tools to study dementia, she just didn't have enough training in science. And so if she wanted to work as a scientist, she needed more education. So she talked to Dean Thompson about it. And he helped her get into the School of Biochemistry at Cambridge to do her PhD. Uh, she had a wonderful time at Cambridge. Here she met two scientists, Drs. Margaret Stephenson and Dorothy Needham, who were some of the very first women to be elected into the Royal Society, which was very encouraging to Ita as a young woman scientist. Arpita: 13:45 That's super cool. I was gonna say two women. That's really like, I guess, not expected. Aarati: 13:52 Yeah. She said they made her realize that quote,"Good science gets recognition regardless of the sex of the scientist." End quote, which I thought was very nice. Arpita: 14:00 I feel like we've maybe had some episodes to the contrary, but... Aarati: 14:04 Yes, I was thinking of Svetlana Mosjov. Yeah, I was. Yes, I was thinking of her. Arpita: 14:10 I do appreciate the sentiment. I do. But yes. Aarati: 14:12 Yeah. I'm glad that that was her takeaway and that she was inspired. Arpita: 14:17 Agree. Aarati: 14:18 Uh, her PhD supervisor was Dr. Malcolm Dixon and Ita really appreciated him because he basically gave her a project and let her go at it and let her figure it out herself. And that really gave her the confidence to believe that she could pursue independent research. So after completing her PhD, she got a staff position at the National Institute for Medical Research or NIMR in Mill Hill, London, studying protein synthesis. And the question Ita was really interested in was whether proteins were translated from RNA in one long continuous strand or whether multiple small segments were translated and then they all came together afterwards. Arpita: 15:00 Mm-hmm. Aarati: 15:00 Because remember, like we don't really know, this is like basic biology. We don't know the answer to this very basic question. Um, and so to look at this, they were working with lactating goats and studying their milk proteins. Arpita: 15:16 Interesting. Okay. Aarati: 15:17 Yeah. So Ita would give the goats short pulses of radio labeled amino acids, which are the building blocks for proteins. And then she would collect the milk, purify the milk protein that she was studying, which was called lactoglobulin. And the theory was that if she had seen certain segments of the protein were made with radiolabeled amino acids and other segments were not, then that would have indicated that the proteins were translated in small pieces and then came together into a long chain later. But that's not what she saw. Instead, she observed that the whole lactoglobulin protein was made with radiolabeled amino acids, so that meant that the proteins were being translated rapidly in one long, continuous piece. Arpita: 16:01 One long chunk. Aarati: 16:02 Yeah. Arpita: 16:02 Yeah. Aarati: 16:03 And this was later confirmed, in, various other ways by other scientists. And ultimately we got the double helix model of DNA, which, you know, that all fit together. So that was a successful project, but Ita had a few issues. One was that she really didn't like working with the goats. Especially there was one named Ursula who she found nearly impossible to catch and milk. Arpita: 16:28 Okay. What are all of these model organisms? Like, I'm just like, what is happening? Like, there's just like. Whatever animal they could get their hands on, like, I just feel like this range of model organisms that we've discussed, I don't even know, this doesn't even count as a model organism, but like. Aarati: 16:42 Yeah, I don't know why goats. I don't know what they were doing, but... Arpita: 16:45 Like, why was it goat milk, like lactating goats, like, Aarati: 16:49 I don't know. I have no idea. Arpita: 16:51 Why are we milking goats? There's no other way to find protein? Aarati: 16:56 Yeah. So that was her problem exactly. She was just like, why are, why am I, these, these goats are so annoying. They don't wanna be milked. I have to chase them around the pen and I have to like try and catch them. And they're so like... ugh, irritating. And I actually watched this YouTube video where one of Ita's friends was talking about her and she said that Ita was a big fan of flora but not of fauna. She really didn't like dogs, cats, babies. Arpita: 17:23 I was about to be like, relatable, but then I was like, wait, wait, wait, wait, wait, wait. Aarati: 17:26 No, no, no. She just didn't like any animals. Arpita: 17:29 What I don't like is animals in the lab. Aarati: 17:31 Yes. Yeah. Arpita: 17:32 Yeah. Aarati: 17:32 Like she just didn't like animals in general, so this was probably even worse for her. Arpita: 17:36 Yeah. Okay. Yeah. Aarati: 17:37 But the second problem was that purifying lactoglobulin or really any milk protein was difficult because milk contains something called casein. And we talked about this briefly in the Wilbur Scoville episode about how when you eat something spicy, drinking dairy products is a great remedy because it contains casein, which is a really sticky molecule and it will surround the capsaicin and wash it away. But because it's so sticky, Ita had a really hard time getting rid of it in order to study the lactoglobulin. Arpita: 18:07 To purify it. Yeah, that makes sense. Aarati: 18:10 So Ita, like you said, was like, there has to be a better way to study protein synthesis than chasing around goats and crystallizing tiny amounts of protein. Arpita: 18:19 Hard agree. Aarati: 18:20 So around this time, she attended a lecture at the NIMR given by an immunologist, Dr. John Humphrey. And his lecture was about antibodies, which Ita knew nothing about at all. So, I know you know this, Arpita, but maybe just for our listeners who kind of need something to form an image in their head like I do, um, Antibodies are proteins that are shaped kind of like the letter Y, and that top part of the Y can detect and bind to other proteins called antigens. And antibodies are naturally programmed to detect foreign invaders like viruses or bacteria that do not belong in our bodies. And once they detect something like that, they can trigger an immune response, which basically tells our body to destroy that invader. So Dr. John Humphrey was giving his lecture and he gave a demonstration of how this worked. He had two clear solutions. One was a solution of purified antibodies, which are the Y shaped proteins. And one was the antigen, which is what the antibodies detect and bind to. And when he mixed the two solutions together, all of the antibodies glommed onto the antigens and formed a precipitate that settled to the bottom of the mixture. Arpita: 19:36 That's cool. Aarati: 19:37 And so when Ita saw this, she's like, that's brilliant. That's such an elegant answer to my protein purification problem because that precipitate that's forming in Dr. Humphrey's flask is mostly antibody. So, if she studied protein synthesis using antibodies instead of lactoglobulin, first of all, she could use any small animal. She didn't have to use goats. She could use rabbits or mice that she didn't have to chase all over the place. And instead of collecting milk, she could instead trigger an immune response so that the animal created antibodies and then she would just have to collect some blood or some serum and then use that same method that Dr. Humphrey just used to precipitate out the antibodies and then you've got pretty much purified antibody protein that she could study. Arpita: 20:25 Oh, interesting. I see. So her protein of choice is now just antibodies. Aarati: 20:30 Yeah, exactly. Arpita: 20:31 Got it. And like a particular antibody or she's just casting a wide net here? Aarati: 20:36 Um, at this point, not yet. Arpita: 20:38 Okay. Aarati: 20:38 I mean, actually throughout her life she kind of hops around different antibodies, but right now she's just like, what antibody can I... Arpita: 20:45 yeah. Aarati: 20:45 Use to study protein synthesis and antibody synthesis. Yeah. So she ran this idea by Dr. Humphrey and he was all for it. He's like, I'll help you however I can. So, Ita asked him, well, since I want to study antibody synthesis, it would be really helpful to know which tissue or organ they're made in. Arpita: 21:04 Right. Aarati: 21:04 And, Dr. Humphrey's like, well, that's a great question. Um, the antibodies are definitely made in a type of white blood cell called plasma cells. And they didn't have the name for it at the time, but today we call them plasma B cells. Um, But as for which tissue they're made in, he didn't know. And so Ita's like, great, let's start there. Arpita: 21:27 Yeah. Aarati: 21:27 So Ita and another scientist Bob White start using guinea pigs to systematically figure out which tissue the antibodies are coming from. They would inject the guinea pig with ovalbumin, which is a protein found in egg whites. And actually, if you have an egg allergy, you're probably allergic to ovalbumin. Arpita: 21:47 Yeah I,, I'm not allergic to this, but I, I do, I did know that because that's when you get the flu shot. They always ask you if you have an egg allergy. Yeah, Aarati: 21:54 We learn about that in like bio and biochemistry because it's a really easy protein or it's, it's really easy to purify. And so it's a very common antigen that's used to create an immune response in lab animals all the time so that scientists can study the immune system. It's like very common. Arpita: 22:10 Yeah. And in vaccine development, which is why they ask you that. Aarati: 22:14 Yeah, that's why they ask you. Exactly. So she uses ovalbumin to trigger an immune response and then collected a tissue sample from whatever tissue they thought might be producing the antibodies. She chopped up the tissue, added radiolabeled amino acids and then collected the antibodies, which if they were being made in that tissue would now be radiolabeled and she could detect that. So if they thought like, hey, maybe the antibodies are being made in the liver, they chopped it up, added radio labeled amino acids, and then look to see if any radio labeled antibodies were made. And in the case of the liver, not many radio labeled antibodies were detected, indicating that they're not being made there. The tissues where she did find the highest amount of radio labeled antibodies were in the lymph nodes, bone marrow, and in the lungs. Arpita: 23:04 Oh, the lungs. Interesting. Aarati: 23:05 Yeah. But they also discovered something called the bystander effect, which is that it wasn't just antibodies that was specific to ovalbumin being formed, but generic antibodies as well. And that was pretty surprising to them at the time. But now we know that when the immune system is highly activated, non specific antibodies are created to help drive the overall immune response. So that's kind of what was happening there. Arpita: 23:29 Right. Aarati: 23:30 And I think that maybe explains why they were seeing antibody synthesis in the lungs. Cuz that's... Arpita: 23:36 That is interesting. I did not know that. Lymph and bone marrow make a lot of sense. That's what we typically think of as like, kind of like hubs for the immune system, but interesting about the lungs. Aarati: 23:50 Yeah, so under Dr. Humphrey, Ita is really making some huge contributions to the field of immunology already. In 1957, a new immunology division was created at NIMR, and Dr. Humphrey was asked to lead it. And so Ita joined him, and they, along with a core group of scientists, became really the founding team for this division. But Ita's still not happy about the fact that she has to do these experiments in animals because she couldn't isolate the specific cells that created the antibodies to ovalbumin and then create a cell line from them. So she couldn't study this in vitro, or in a petri dish. And that's because the lymph nodes contain a whole bunch of different cells, So the cells that Ita is interested in are the B cells. And there are two types of B cells. There's the plasma B cells, which I mentioned are the ones that make and secrete the antibodies, and there are memory B cells that can live for years just hanging out, and their job is to remember a specific pathogen and trigger an immune response if it ever enters your body. So, there will be a memory B cell for ovalbumin, which was what Ita was triggering to start multiplying and create a bunch of plasma B cells, which would then create the ovalbumin specific antibodies. But there are also other memory B cells for like flu virus or bacterial pathogens that would all just kind of be hanging out together in the lymph node. And so if you only wanted to collect the B cells that are responsible for creating, like, one type of antibody, it's really hard to separate. them out from the lymph node from all the other cells. Arpita: 25:32 Like if you're doing this in the animal, in vivo, that's really hard to do. Yeah, that makes sense. Aarati: 25:36 And then if you wanted to take those cells and put them like in a petri dish and then kind of create a line that you could study and just take these experiments out of animals and not have to deal with animals at all, it's really hard to do that. Fortunately, around this time at the NIH, A group led by Dr. Mike Potter had discovered a cancerous cell line in which the plasma cells were secreting antibodies out of control. So cancerous, right? Arpita: 26:03 Wow. Okay, great. Love that serendipity. Aarati: 26:06 Yes, exactly. And so these plasma cells would produce antibodies, both in vivo, in mice, and in vitro. Arpita: 26:15 Oh, great. Aarati: 26:16 Yeah. Ita's like, perfect. Exactly what I needed. Yeah. That's what I need to study antibody synthesis and how these proteins are being synthesized. That's great. And this became a really valuable tool for her for studying antibody formation. And I'm not. going to go super into detail about all of her experiments here, but once Dr. Potter sent them the cell line, Eda was really able to pin down like some of the nitty gritty details as to what parts of the antibodies were formed first and how the different parts of the antibodies come together to form that Y structure. So she really like nailed down antibody synthesis. Arpita: 26:54 That's super cool. Aarati: 27:00 Hi everyone. Aarati here. I hope you're enjoying the podcast. If so, and you wish someone would tell your science story, I founded a science communications company called Sykom, that's S Y K O M, that can help. Sykom blends creativity with scientific accuracy to create all types of science communications content, including explainer videos, slide presentations, science writing, and more. We work with academic researchers, tech companies, non profits, or really any scientist to help simplify your science. Check us out at sykommer. com. That's s y k o m m e r dot com. Okay back to the story. So now Ita's been working on protein synthesis and particularly antibody synthesis for nearly a decade. She decides to take a bit of a step back and revisit her biochemistry roots. So from 1961 to 62, she did a sabbatical at Harvard Medical School, and here she was reminded about our good friend, Elie Metchnikoff, who you covered in Episode 6. At this point, it's been about a hundred years since he discovered macrophages, and people knew that macrophages were another type of white blood cells that were different from plasma B cells but still related to the immune system because they went around engulfing and degrading foreign invaders in the body. Arpita: 28:29 I also feel like macrophages are conceptually just so easy to understand. Like you very much think about them as like Pac- man, you know? Like it just makes a lot of sense that you have something that's just like eating trash. Aarati: 28:40 Yes. Arpita: 28:41 And it really is not that much more complicated than that. Like that is really the science is that it's just kind of engulfing things and then degrading them. Aarati: 28:49 Yes. Arpita: 28:50 I feel like once you start getting into antibodies and the rest of immunology, like everything hits the fan. But... Aarati: 28:57 Yeah, yeah, no, macrophages are simple. Arpita: 29:00 Macrophages we can do. We can do macrophages. Aarati: 29:02 Yeah. So that's what people knew. They're like, macrophages go around and if it runs into like a foreign bacterial cell or virus, it'll eat it and degrade it. And so Ita was like, huh, good point. I wonder what a macrophage would do if it encountered a foreign antigen. So just like a protein that, you know, didn't belong in the body, would it just gobble it up or was there's some way that it could trigger an immune response or at least spread the information that it had encountered something foreign to... Arpita: 29:31 Yeah. Aarati: 29:32 ...the other immune cells, so that the other immune cells were like aware that this thing was in your body. So she and another scientist, Joan Rhodes fed a radio labeled large antigen protein to macrophages. And they were able to observe that it rapidly broke down the antigen into smaller protein fragments. And then a few years later, a postdoc fellow, Emil Unanue joined Dr. Humphrey's group and started working on the macrophage experiments with Ita. And together they discovered that they could use macrophages to jumpstart the immune system. So if they gave the macrophages an antigen, and the macrophages engulfed it and degraded it and then they took those macrophages and put them in mice and triggered an immune response in the mice, the immune response happened a lot faster than mice that didn't get the macrophages. So, they were like, huh, that's interesting. They published this finding, but they didn't know how to explain it. They were just like, yeah, somehow these macrophages are helping facilitate the immune response, but we don't know how. And so a lot of scientists were really skeptical about this. But a few years later, Emil went back to Harvard. And he really nailed down that what these macrophages were doing was they were keeping small parts of the antigen so that they could show it to a type of immune cell called helper T cells, which, as the name suggests, help trigger the immune response. Arpita: 31:08 Yeah, it's actually like kind of cute. I feel like when macrophages break stuff down and they're just like, look what I have, like, look what I found. Aarati: 31:14 Yeah. Arpita: 31:14 And look what I have. What do we do now? Like, what do we do? I have these little pieces. I started to break it down, but like, what do we do now? Aarati: 31:23 Yeah, I saved this for you. I thought you might find it interesting. Arpita: 31:27 I thought you would like it. What do we do now? Aarati: 31:31 I do have to say, immunology diagrams are really cute. Arpita: 31:34 They are real cute. Aarati: 31:35 All the little soldiers, and all the like, little helper T cells. Arpita: 31:39 The little cartoons are extremely adorable, I will say. Immunology itself, real tough for me. I won't lie. But the little cartoons are cute Aarati: 31:49 Cartoons are great. Um, but there's another postdoc that eat a mentored Hugh McDevitt, who figured out that there's a specific molecule called the major histocompatibility class two molecules on the self surface of the macrophage, so MHC II molecules. Those are on the cell surface of the macrophage, and that's what it uses to present the antigen to the helper T cells. So it's like the little arm holding out the antigen to the helper T cells to show it to them. Arpita: 32:23 Or the little plate with all the little cookies on it. Aarati: 32:26 Exactly. Yeah, so this is like a huge breakthrough for immunology. Like, this is really foundational work, right? Like, we learned about MHC class 2. Arpita: 32:36 This is like all very just like Immunology 101, for sure. Aarati: 32:41 Exactly. So it's very foundational work being done. But Ita declined authorship on both Emil and Hugh's papers because she didn't think she had contributed enough to be an author. She was just like, I just mentored you and like pushed you in the right direction. I didn't actually do anything. Arpita: 32:57 I have never met a PI like that in real life, but continue. Aarati: 33:00 But both of them have said on numerous occasions that they would not, they would not have figured this out without her, like, they would not be where they are today without her. So I think because of that, a lot of times, like, people don't know about Ita Askonas You know, she just like, was like, uh, no, don't put me on that paper. You really did all the work. Arpita: 33:20 I've put people on papers for less. Aarati: 33:22 Yeah, right? Yeah. Arpita: 33:26 But, like, the random person who, like, sometimes shows up in the lab every once in a while, the fellow who, like, isn't really part of the lab anymore, they're on the paper. Yeah. Like, Aarati: 33:34 The person who took your plate out of the incubator when you were in a meeting, it's like... Yeah, but Ita just like helped so many graduate students and postdocs and every single one of them was like, she could be really tough on you and very challenging, but in the end the people that she helped mentor became better scientists because of it. So it's like a theme throughout her life that she was just like, this helping hand, this force that mentored people. Arpita: 34:02 It's best case scenario. Aarati: 34:04 Yep. So while she's helping with the project on macrophages. She also continued to work on B cells, and she had another scientist, Alan Williamson, did experiments that showed that a single B cell will only form a single specific type of antibody. So remember, there are two types of B cells. There's the memory B cells and each memory B cell remembers one specific pathogen, whether it's a flu virus or a bacterial pathogen or ovalbumin. And so when the immune response is triggered to the specific thing that that memory B cell remembers, it starts to divide and it makes more memory B cells. But it also makes plasma B cells, which will produce antibodies to that specific pathogen, and so because of that, if you look at a single plasma B cell, it only makes one type of antibody. So they figured that out. Arpita: 35:01 It is kind of crazy. And you think of how many antigens you encounter. It's constant. It's like literally anything is an antigen. Like it could be a virus. It could be pollen. It could be dander. It could be anything that causes any sort of immune reaction. Aarati: 35:19 Yeah, it could be a little bug that you inhale by accident. Arpita: 35:22 Exactly. Exactly. It could be anything. It could be something on a doorknob. It could be. And so you think about truly how many antigens we encounter and then how many corresponding B cells you have. It actually is quite crazy. And so when you think about your whole immune system, it like incorporates all of these things in the memory of all of these past antigens. Aarati: 35:43 And I think that's why they had such a hard time like isolating any specific B cell that they wanted to study from the lymph nodes, because there are just so many things, you know, that your body is programmed to remember. But actually they kind of succeeded. So Ita and Williamson and a third scientist, Brian Wright, are also credited with developing a way to clone memory B cells in mice. And so, this was huge because no one had been able to do that before either in vitro or in vivo, like she had been working with the cancerous plasma cell line for that purpose. Um, but they finally figured out a method to do it and they were able to clone or create copies of a single memory B cell. And because they did that, they essentially produced the first monoclonal antibodies. So mono means one and clone refers to like identical cells from a single parent And so, since the cells making the antibodies are identical, the antibodies that they make are also identical. So. Um, they were doing this really as a larger project to figure out how long a memory B cell would survive and divide before dying out. They didn't really set out to make monoclonal antibodies, but they're credited really with making the first ones kind of as a byproduct. Arpita: 37:10 Yeah. Aarati: 37:10 But just to like provide some context for how important monoclonal antibodies are: a few years later, two scientists, Cesar Milstein and George Kohler won the Nobel Prize for creating an immortal cell line that produced monoclonal antibodies. So I don't think she was like involved in that, but they won a Nobel Prize for basically doing what she had done, but just creating an immortal cell line of that. Scientists use monoclonal antibodies to target specific cancer cells to provide targeted drug treatment, or they can just be used to mark the cancer cells so your body knows to destroy it. They're used in autoimmune disorders. Uh, they're used to test blood and tissue compatibility for organ donation. They're used in diagnostic tests. They're used like in pregnancy diagnostics. So like pretty much any field that you can think of, we use monoclonal antibodies. They were used to like help prevent coronavirus from invading our cells.. Like everything. Arpita: 38:10 It's everywhere. It's very like, um, what is the word I'm looking for? Aarati: 38:16 Ubiquitous? Arpita: 38:17 Yes. Yes. Yes. Aarati: 38:23 They are. Arpita: 38:23 I was going to say evasive, but I think I meant pervasive. And then I was like, oh yes. Ubiquitous is actually the right word. Aarati: 38:30 Pervasive is good too. So, yeah. They're credited with creating, like, kind of the first monoclonal antibodies, which, so it's huge. Arpita: 38:40 I did not know that. For, like, how common monoclonal antibodies are and how much they come up in conversations about literally any kind of therapy, disease, like, I feel like it comes up all the time. I definitely didn't know that it was discovered kind of by accident. Not an accident, but really just, like, as a, you know, this unintentional consequence. Aarati: 38:59 Yeah, exactly. But yeah, in 1973, Ida was a elected to be a fellow of the Royal Society, which as we know is a huge honor. She joined those two women, yeah, that she had met. Although I think like at this point, she's like the 27th woman or something to be inducted into the Royal Society. In 1976, Dr. Humphrey left the NIMR and Ita took over as head of the immunology division. And at this point, Ita had spent 21 years studying antibodies and their synthesis in B cells. And so she decides, you know what, I've had enough of studying chemical antigens. I really want to study real immune responses to real infectious pathogens. So she started working on two projects. The first was looking at a disease called African trypanosomiasis, which is also known as sleeping sickness. It's a lot, a lot easier to say. It's caused by a protozoan parasite that is spread by the tsetse fly and somehow this parasite is able to evade and inhibit the immune system. So she was really intrigued by that. Eventually the person who's infected is unable to fight off the disease and they fall into a coma and die. So that's why it's called sleeping sickness. Arpita: 40:22 Okay. Aarati: 40:22 Yeah. Arpita: 40:23 That's aggressive. Aarati: 40:24 Yeah, so Ita and her students spent years trying to figure out like what's going on and they were able to untangle some of it. They were able to show like certain things about how macrophages that had engulfed a protozoan went through profound metabolic changes and you could used that macrophage to infect an otherwise healthy mouse. And they found that like known regulators of the immune system were secreted during the infection, but she didn't really come any closer to finding a way to reverse the immune system suppression. And we do have medications today that can kill the parasite, but they have to be administered before the parasite is able to shut down your system. So Arpita: 41:07 Oh, so if it, if it goes past some point of no return, you're just. Aarati: 41:11 Yeah, I think it's like within 30 days or something I read that you have to take the medication. Arpita: 41:17 So how do you know you have it? Aarati: 41:19 Oh, I think there's like a whole host of symptoms because your immune system is trying to... Arpita: 41:23 it's like shutting down. Aarati: 41:24 Yeah, fever and fatigue and like all this kind of stuff. Yeah. Arpita: 41:28 Okay, so then you go and you get like some test and then they have to administer this ASAP. Aarati: 41:32 Yeah, I think so. Arpita: 41:34 That's crazy. Aarati: 41:36 Yeah, so, I mean, they found out a lot about this disease, but in her long list of successes, this was maybe the only kind of, like, you know, we didn't really figure out anything groundbreaking. Arpita: 41:50 Like, there was no, like, cure, basically. Aarati: 41:53 Yeah, her other project, though, was on the influenza virus, and this, again, was groundbreaking work in immunology. So, she started studying yet another type of white blood cell called cytotoxic toxic T cells, which we affectionately know as killer T cells. Arpita: 42:09 Killer T cells. Aarati: 42:10 Yes. So, Yeah, if you break down the word cytotoxic, it literally means toxic to cells. And that's what T cells do. They find a cell that's a foreign invader or cancerous cell or a cell that's been infected with a virus and it kills it before it can replicate and become an issue. But what Ita and her students discovered was that, T cells aren't like B cells in that they don't go after one specific type of virus or antigen. The same T cell could recognize and kill multiple different types of influenza strains. And so it's not a total free for all, there are like some rules, like there's two categories of influenza, A and B, and within those categories there's a bunch of different strains, but one cytotoxic T cell could recognize all the strains in influenza A, for example. And one of her students, Alaine Townsend, managed to clone cytotoxic T cells, which again was the first time anyone's been able to do that. And she and Alaine were able to show that the T cells weren't actually recognizing the infected cell, they were actually recognizing The viral protein itself. And that was weird to them because they were like, how can a T cell detect a virus that's inside of a body cell? Like you would think that they're detecting something on, maybe on the cell surface. Yeah. Um, so Alain finished up his PhD and moved to Oxford where he kept on working on this. And he went on to show that. Cells that are infected with a virus can grab a small fragment of the viral protein from inside themselves and present it on their cell surface using, again, a major histocompatibility complex molecule. It's MHC 1 this time. So once again, presenting this like, Hey, look, there's this thing inside me. And so the cytotoxic T cell sees a cell presenting a viral protein fragment on its cell surface with the MHC 1 molecule, and that's how it knows to kill it. And again, figuring out how T cells worked was huge and is foundational to how we make vaccines against these kinds of viral infections. So, another huge contribution to immunology, but once again, Ita declined authorship on this paper because she felt like she hadn't actually, like, done anything. She was just like, no, it's all you. You did everything, Alain. Arpita: 44:40 That's nuts. Aarati: 44:41 Yeah. Yeah. So this is something like everyone said about Ida. She was extremely humble, never bragged about her accomplishments. And in fact, Dame Bridget Ogilvie, her friend, said that even though Ida was extremely close to her family, since she didn't talk about her work much, none of them really understood, like, what a giant in her field she was. Arpita: 45:04 Mm. Aarati: 45:04 And In fact, they kind of seem to be like, "Aw, you're a scientist. Like we love that for you. I mean, good job. And they're like, you're not like your cousin, Peter, who like founded a music and art agency. Like he's amazing. Uh, we can barely even trust you to cook dinner." And Ita's just like, yep."I hate cooking. I'll do the dishes." And she didn't say like a single word about her work or what she was doing. Arpita: 45:30 Couldn't be me. I... Aarati: 45:31 yeah. Arpita: 45:31 Couldn't be me. I think I'm too annoying. Aarati: 45:34 You worked hard for it, though. Like, come on, you deserve respect. But her friend Bridget would jokingly say that actually Ita was being very clever by lowering her family's expectations of her so she could just duck out of certain chores and responsibilities, which I was like Arpita: 45:50 That's smart. Yeah. She's, she's living in, you know, 2038 for sure. She's really just, Aarati: 45:57 She's playing chess. We're all playing checkers. Arpita: 46:00 Yeah, exactly. Aarati: 46:02 Yeah. So Ita retired in the late 1980s, but she stayed active in the field discussing science and encouraging new students to pursue immunology. In 2007, Ita was elected to be a foreign associate of the U. S. National Academy of Sciences, and she was awarded the Robert Koch Medal for her lifelong contributions to immunology. And in 2012, she received an honorary doctorate from Cambridge, which she was very proud of. Arpita: 46:33 That's amazing. Wow, she lived a really long time, wasn't she born in 1923? Aarati: 46:39 Yes. Arpita: 46:39 19- Aarati: 46:40 Yeah. Arpita: 46:40 Yeah. Wow. Aarati: 46:41 Yeah. The following year, in 1913, she did pass away at the age of 89. Arpita: 46:47 Wow. Aarati: 46:48 Uh, she never got... yeah. Like, she lived a long life, and she was very active during it. She never got married or had any children, but the reason I think she really deserves the title of the mother of immunology is just the sheer number of people that she mentored and supported who then went on to make such amazing contributions. Arpita: 47:07 Their own contributions. Yeah, exactly. That is, I know that was like noticing that as you were telling the story too, like she was like, there was a postdoc and there was a mentor and there was this PhD student and there was another PhD student and there was another institution and another person. And so it's actually really, really crazy how many people there were. Aarati: 47:22 Yeah. Arpita: 47:23 And like sometimes people in science will talk about like your family tree. Like your scientific family tree and like I feel like having her in your scientific family tree was probably like A) just clout but then B) like I'm sure you got so much guidance and shaping for how you think about questions and experiments and roadblocks and I'm sure that must have been really influential. Aarati: 47:44 Yeah, and, like, the ones that I mentioned in the story is just, like, barely scraping the surface of the iceberg. Like, I was reading her, like, obituary and, like, her biography, and in some places there was just, like, a list of names. It's like, she mentored this person, and this person, and this person, and this person, and this person. I'm just like, oh, my God. It's like Arpita: 48:03 Yeah, and you think about, too, like, I feel like immunology is kind of in its heyday, like with how many therapies and new drugs are being produced that are either using like monoclonal antibodies or, you know, working against all of these different diseases, including, you know, um, autoimmune diseases is what I'm trying to say, and I feel like there's, there's so many cool breakthroughs there. And so like, just like understanding the foundations of immunology, just knowing how many more people have been working on it and like, also knowing that we're truly like kind of in a heyday of immunotherapy is really cool. Aarati: 48:41 Yeah. And I was just like, also very surprised by just how she was just all over everything. She was like over plasma B cells and antibodies and cytotoxic T cells and macrophages. It was like, there was no part of the immune system that she didn't touch, I felt like so I was just really surprised. Arpita: 49:01 And there's a lot. Aarati: 49:02 Yeah, there's so much like on one hand, I was really surprised that she doesn't get more recognition. But on the other hand, it does seem like she declined a lot of recognition, you know, Arpita: 49:12 Interesting choice. But yeah, yeah. Aarati: 49:14 Yeah. She was just like, no, I don't need it. So yeah, that's her story. I really enjoyed like reading about it. I feel like. I learned a lot more about immunology than I knew before. Arpita: 49:26 Honestly, same. And I feel like I sort of came in with the baseline level of understanding, and I still did. Like, I definitely didn't know the thing about the monoclonal antibodies, which is really, really cool. Aarati: 49:36 Yeah. Arpita: 49:37 Great story. I loved it. Aarati: 49:38 Thank you. Arpita: 49:39 We love a little girl power. Aarati: 49:41 Yes. We need it. Arpita: 49:43 We do need it. Aarati: 49:43 We always need it. Arpita: 49:48 Thanks for listening. If you have a suggestion for a story we should cover or thoughts you want to share about an episode, reach out to us at smartteapodcast. com. You can follow us on Instagram and Twitter@smartteapodcast and listen to us on Spotify, Apple Podcasts, and or wherever you get your podcasts. And leave us a rating or comment. It really helps us grow. Special thanks to our editor, James Fixx. New episodes are released every other Wednesday. See you next time!